Skip to main content
Log in

The arachidonic acid cascade

The prostaglandins, thromboxanes and leukotrienes

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Certain polyunsaturated fatty acids, such as arachidonic acid, are metabolized by oxygenation into a large family of biologically active substances, the prostanoids. These include the prostaglandins, thromboxanes, prostacyclins, leukotrienes and also a number of related compounds. Oxygenation can take place at many different positions of arachidonic acid. A cyclo-oxygenase introduces oxygen at C-11 and converts the resulting peroxy compound into a 9, 11-endoperoxide structure. The cyclic peroxides thus formed, PGG2 and PGH2, are highly potent compounds and are the immediate precursors of the prostaglandins, thromboxanes and prostacyclin. Other enzymes, the lipoxygenases, may instead introduce oxygen at C-5, C-8, C-9, C-12 or C-15: further conversions from, for example, the initially formed 5- or 15-hydroperoxy acids may lead to the leukotrienes. The prostanoids display strong and varied biological activities, and have effects on numerous processes in the body. In some pathological conditions the prostanoids play important roles. For example, certain products of the arachidonic acid cascade are considered to be mediators of the inflammatory response: they are formed during the process, contribute to the symptoms of erythema, vascular leakage, fever, pain and chemotaxis, and inhibition of their biosynthesis can be achieved at different levels by the anti-inflammatory drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Burr, G. O., andM. M. Burr. 1930. On the nature and role of fatty acids essential in nutrition.J. Biol. Chem. 86:587–621.

    Google Scholar 

  2. Kurzrok, R., andC. C. Lieb, 1930. Biochemical studies of human semen: action of semen on human uterus.Proc. Soc. Exp. Biol. Med. 28:268–272.

    Google Scholar 

  3. Bergstrom, S., F. Dressler, R. Ryhage, B. Samuelsson, andJ. Sjovall. 1962. The isolation of two further prostaglandins from sheep prostate glands.Arkiv Kemi 19:563–567.

    Google Scholar 

  4. Bergstsöm, S., R. Ryhage, B. Samuelsson, andJ. Sjövall. 1963. Prostaglandins and related factors. The structures of prostaglandins E1, F1 alpha and F1 beta.J. Biol. Chem. 238: 3555–3564.

    Google Scholar 

  5. van Euler, U. S. 1935. Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekretes.Klin. Wochenschr. 33:1182–1183.

    Google Scholar 

  6. Nelson, N. A. 1974. Prostaglandin nomenclature.J. Med. Chem. 17:911–918.

    Google Scholar 

  7. Van Dorp, D. A., R. K. Beerthuis, D. H. Nugteren, andH. Vonkeman. 1964. The biosynthesis of prostaglandins.Biochim. Biophys. Acta 90:204–207.

    Google Scholar 

  8. Bergström, S., H. Danielsson, andB. Samuelsson. 1964. The enzymatic formation of prostaglandin E2 from arachidonic acid.Biochim. Biophys. Acta 90:207–210.

    Google Scholar 

  9. Van Dorp, D. A., R. K. Beerthuis, D. H. Nugteren, andH. Vonkeman. 1964. Enzymatic conversion of all-cis-polyunsaturated fatty acids into prostaglandins.Nature 203:839–841.

    Google Scholar 

  10. Bergström, S., H. Danielsson, D. Klenberg, andB. Samuelsson. 1964. The enzymatic conversion of essential fatty acids into prostaglandins.J. Biol Chem. 239:PC4006-PC4008.

    Google Scholar 

  11. Awanda Rao, G., K. Siler, andE. C. Larkin. 1979. Diet-induced alterations in the discoid shape and phospholipid fatty acid compositions of rat erythrocytes.Lipids 14:30–38.

    Google Scholar 

  12. Lands, W. E. M., M. Inoue, Y. Sugiura, andH. Okuyama. 1982. Selective incorporation of polyunsaturated fatty acids into phosphatidylcholine by rat liver microsomes.J. Biol. Chem. 257:14968–14972.

    Google Scholar 

  13. Lands, W. E. M., andB. Samuelsson. 1968. Phospholipid precursors of prostaglandins.Biochim. Biophys. Acta 164:426–429.

    Google Scholar 

  14. Irvine, R. F. 1982. How is the level of free arachidonic acid controlled in mammalian cells?Biochem. J. 204:3–16.

    Google Scholar 

  15. Blackwell, G. J., R. Carnuccio, M. Dirosa, R. J. Flower, L Parente, andP. Persico. 1980. Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocorticoids.Nature 287:147–149.

    Google Scholar 

  16. Samuelsson, B., E. Granström, K. Green, M. Hambehg, andS. Hammarström. 1975. Prostaglandins.Annu. Rev. Biochem. 44:669–695.

    Google Scholar 

  17. Yamamoto, S., S. Okhi, N. Ogino,et al. 1980. Enzymes involved in the formation and further transformations of prostaglandin endoperoxides,Adv. Prostaglandin Thromboxane Res. 6:27–34.

    Google Scholar 

  18. Bergström, S., L. A. Carlson, andJ. R. Weeks. 1968. The prostagiandins: afamily of biologically active tipids.Pharmacol. Rev. 20:1–48.

    Google Scholar 

  19. Hamberg, M., J. Svensson. andB. Samuelsson. 1975. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides.Proc. Natl. Acad. Sci. USA.,75:2994–2998.

    Google Scholar 

  20. Johnson, R., D. Morton, J. Kinner,et al. 1976. The chemical structure of prostaglandin X (prostacyclin).Prostagiandins 12:915–928.

    Google Scholar 

  21. Moncada, S., andJ. R. Vane. 1979. Mode of action of aspirin-like drugs.Adv. Intern. Mecl. 24:1–22.

    Google Scholar 

  22. Murphy, R. C., S. H. Ammarström, andB. Samuelsson. 1979. Leukotriene C: a slow-reacting substance from murine mastocytoma cells.Proc. Natl. Acad. Sci. USA. 76:4275–4279.

    Google Scholar 

  23. Samuelsson, B. 1980. The leukotrienes: a novel group of compounds including SRS-A and mediators of inflammation.In SRS-A and the leukotrienes. P. J. Piper, editor. John Wiley & Sons, New York. 45–64.

    Google Scholar 

  24. Samuelsson, B. 1982. Leukotrienes: a new group of biologically active compounds.In Advances in pharmacology and therapeutics II. Biochemical immunological pharmacology. H. Yoshida, Y. Hagihara, and S. Ebashi, editors. Pergamon Press, Oxford and New York.4:55–75.

    Google Scholar 

  25. Hansson, G., O. Radmark, andC. Malmsten. 1983. The leukotrienes and other lipoxygenase products.In The prostagiandins and related compounds. New Comprehensive Biochemistry. C. R. Pace-Asciak, and E. Granström. editors. Elsevier/North Holland, Amsterdam.5:127–169.

    Google Scholar 

  26. Vane, J. R., andS. H. Ferreira, editors. 1978. Inflammation. Handbook of experimental pharmacology, vol. 50/1. Springer Verlag, Berlin, Heidelberg, New York.

    Google Scholar 

  27. Weissmann, G., B. Samuelsson, andR. Paoletti. editors. 1979. Advances in inflammation research, vol. I. Proceedings of the First International Congress on Inflammation, Bologna, Italy, 1978. Raven Press, New York.

    Google Scholar 

  28. Trang, L. E. 1980. Prostagiandins and Inflammation.Semin. Arthritis Rheum. 9:153–190.

    Google Scholar 

  29. Gryglewski, R. J. 1981. Molecular mechanisms of inflammation.Eur. J. Rheumatol. Inflamm. 4:153–159.

    Google Scholar 

  30. Kuehl, F. A. Jr., andR. W. Egan. 1980. Prostagiandins, arachidonic acid, and inflammation.Science 210:978–984.

    Google Scholar 

  31. Goetzl, E. J. 1981. Oxygenation products of arachidonic acid as mediators of hypersensitivity and inflammation.Medical Clinics North America 65:809–828.

    Google Scholar 

  32. Malmsten, C. 1981. Some aspects of prostagiandins. thromboxanes and leukotrienes in inflammation.In Cellular aspects of inflammations. P. Venge and A. Eindbom, editors. Almqvist & Wiksell Int. Stockholm. 73–102.

    Google Scholar 

  33. Weissmann, G. 1982. The biochemistry of inflammation: rheumatoid arthritis and antiinflamrnatory drugs.J. Miss. Stale Med. Assoc. 23:66–73.

    Google Scholar 

  34. Weisssmann, G., C. Serhan, H. M. Korchek, andJ. E. Smolen. 1982. Neutrophils: release of mediators of inflammation with special reference to rheumatoid arthritis.Ann. N. Y. Acad. Sci. 389:11–24.

    Google Scholar 

  35. Flower, R. J. 1977. The role of prostagiandins in inflammatory reactions,Naunyn-Schmiedebergs Arch. Pharmacol. 297 (suppl.):S77-S79.

    Google Scholar 

  36. Lewis, G. P. 1977. Prostagiandins in inflammation.J. Reticuloend. Soc. 22:389–402.

    Google Scholar 

  37. Moncada, S., S. H. Ferreira, andJ. R. Vane. 1978. Pain and inflammatory mediators.In Inflammation. Handbook of experimental pharmacology, vol 50/1. J. R. Vane, and S. H. Ferreira, editors. Springer Verlag, Berlin, Heidelberg, New York. 588–616.

    Google Scholar 

  38. Higgs, G. A., S. Moncada, andJ. R. Vane. 1980. The mode of action of anti-inflammatory drugs which prevent the peroxidation of arachidonic acid.Clin. Rheum. Dis. 6:675–693.

    Google Scholar 

  39. Williams, T. J., andM. J. Peck. 1977. Role of prostaglandin-mediated vasodilation in inflammation.Nature 270:530–532.

    Google Scholar 

  40. Williams, T. J. 1979. Prostaglandin E2, prostaglandin I2 and the vascular changes of inflammation.Br. J. Pharmacol. 65:517–524.

    Google Scholar 

  41. Higgs, G. A., J. A. Salmon, andJ. A. Spayne. 1981, The inflammatory effects of hydroperoxy and hydroxy acid products of arachidonate lipoxygenase in rabbit skin.Br. J. Pharmacol. 74:429–433.

    Google Scholar 

  42. Drazen, J. M., F. K. Austen.R. A. Lewis,et al. 1980. Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro.Proc. Natl. Acad, Sci. USA 77: 4354–4358.

    Google Scholar 

  43. Hedqvist, P., S.-E. Dahlen, L. Gustafsson, S. Hammarström, andB. Samuelsson. 1980. Biological profile of leukotrienes C4 and D4.Acta Physiol. Scand. 110:331–333.

    Google Scholar 

  44. Williams, T. J., andP. J. Piper. 1980. The action of chemically pure SRS-A on the microcirculation in vivo.Prostaglandins 19:779–789.

    Google Scholar 

  45. Dahlen, S.-E., J. Björk, P. Hedqvist,et al. 1981. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response.Proc. Natl. Acad. Sci. USA 78:3887–3891.

    Google Scholar 

  46. Wedmore, C. V., andT. J. Williams. 1981. Control of vascular permeability by polymorphonuclear leukocytes in inflammation.Nature 289:646–650.

    Google Scholar 

  47. Björk, J., P. Hedqvist, andK. E. Arfors. 1982. Increase in vascular permeability induced by leukotriene B4 and the role of polymorphonuclear leukocytes.Inflammation 6:189–200.

    Google Scholar 

  48. Feldberg, W., andA. S. Milton. 1978. Prostaglandins and body temperature.In Inflammation. Handbook of experimental pharmacology, vol. 50/1. J. R. Vane, and S. H. Ferreira, editors. Springer Verlag, Berlin, Heidelberg, New York. 617–656.

    Google Scholar 

  49. Ferreira, S. H. 1972. Prostaglandins, aspirin-like drugs and analgesia.Nature New Biol. 240:200–203.

    Google Scholar 

  50. Ferreira, S. H., andM. Nakamura. 1979. Prostaglandin hyperalgesia. A cAMP/Ca2+(−) dependent process.Prostaglandins 18:179–190.

    Google Scholar 

  51. Juan, H. 1978. Prostaglandins as modulators of pain.Gen. Pharmacol. 9:403–409.

    Google Scholar 

  52. Juan, H. 1979. The pain-enhancing effect of PGI2,Agents Actions (Suppl.)4:204–212.

    Google Scholar 

  53. Smith, M. J. H., A. W. Ford-Hutchinson, andM. A. Bray. 1980, Leukotriene B4. a potential mediator of inflammation.J. Pharm. Pharmacol. 32:517–518.

    Google Scholar 

  54. Palmer, R. M. J., R. J. Stephney, G. A. Higgs, andK. E. Eakins. 1980. Chemokinetic activity of arachidonic acid lipoxygenase products on leukocytes of different species.Prostaglandins 20:411–418.

    Google Scholar 

  55. Malmsten, C. L., J. Palmblad, A. M. Uden, O. Radmark, L. Engstedt, andB. SamUelsson. 1980. Leukotriene B4: A highly potent and stereospecific factor stimulating migration of polymorphonuclear leukocytes.Acta Physiol. Scand. 110:449–451.

    Google Scholar 

  56. Ford-Hutchinson, A. W., M. A. Bray, M. V. Doig, M. E. Shipley, andM. J. H. Smith. 1980. Leukotriene B4, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes.Nature 286:264–265.

    Google Scholar 

  57. Bray, M. A., A. W. Ford-Hutchinson, andM. J. H. Smith. 1981. Leukotriene B4: an inflammatory mediator in vivo.Prostaglandins 22:213–222.

    Google Scholar 

  58. Lewis, R. A., E. J. Goetzl, J. M. Drazen, N. A. Soter, K. F. Austen, andE. J. Corey. 1981. Functional characterisation of synthetic leukotriene B and its stereoisomers.J. Exp. Med. 154:1243–1248.

    Google Scholar 

  59. Björk, J., S.-E. Dahlen, P. Hedqvist, andK. E. Arfors. 1982. Leukotrienes B4 and C4 have distinct microcirculatory actions in vivo.Adv. Prostaglandin Thromboxane Leukotriene Res. 12:1–6.

    Google Scholar 

  60. Lindbom, L., P. Hedqvist, S.-E. Dahlen, J.-A. Lindgren, andK. E. Arfors. 1982. Leukotriene B4 induces extravasation and migration of polymorphonuclear leukocytes in vivo.Acta Physiol. Scand. 116:105–108.

    Google Scholar 

  61. Hamberg, M., andC. E. Jonsson. 1973. Increased synthesis of prostaglandins in the guineapig following scalding injury.Acta Physiol. Scand. 87:240–245.

    Google Scholar 

  62. Higgs, G. A., andJ. A. Salmon. 1979. Cyclooxygenase products in carrageenin-induced inflammation.Prostaglandins 17:737–746.

    Google Scholar 

  63. Jonsson, C. E., Y. Shimizu, B. Fredholm.E. Granström, andE, Oliw. 1979. Efflux of cyclic AMP, prostaglandins E2 and F2 alphs, and thromboxane B2 in leg lymph of rabbits after scalding injury.Acta Physiol. Scand.107:377–384.

    Google Scholar 

  64. Katori, M., Y. Harada, K. Tanaka, H. Miyazakl M. Ishibashi, andY. Yamashita. 1980. Changes of prostaglandin and thromboxane levels in pleural fluid of rat carageenininduced pleurisy.Adv. Prostaglandin Thromboxane Res. 8:1733–1737.

    Google Scholar 

  65. Robinson. H. J., andJ. L. Granda. 1974. Prostaglandins in synoval inflammatory disease.Surg. Forum 25:476–477.

    Google Scholar 

  66. Robinson. D. R., M. B. McGuire, andL. Levine. 1975. Prostaglandins in rheumatic diseases.Ann. N. Y. Acad. Sci. 256:318–329.

    Google Scholar 

  67. Bombardieri, S., O. Dimunno, C. Patrono, D. Grossi-Belloni.G. Ciabattoni, andG. P. Pasero. 1975. Radioimmunoassay measurement of prostaglandin (PG) F1 alpha and F2 alphs levels in human synovial fluid.Scand. J. Rheumatol. 8 (suppl.):26–10.

    Google Scholar 

  68. Trang, L. E., E. Granström, andO. Lövgren. 1977. Levels of prostaglandins F2 alphs and E2 and thromboxane B2 in joint fluid in rheumatoid arthritis.Scand. J. Rheumatol. 6:151–156.

    Google Scholar 

  69. Robinson, D. R., J. M. Dayer, andS. M. Krane. 1979. Prostaglandins and their regulation in rheumatoid inflammation.Ann. N. Y. Acad. Sci. 332:279–294.

    Google Scholar 

  70. Klickstein. L. B., C. Shapleigh, andE. J. Goetzl. 1980. Lipoxygenation of arachidonic acid as a source of poiymorphonuclear leukocyte chemotactic factors in synovial fluid and tissue in rheumatoid arthritis and spondyloarthritis.J. Clin. Invest. 66:1166–1170.

    Google Scholar 

  71. Davjdson, E. M., S. A. Rae, andM. H. J. Smith. 1982. Leukotriene B4 in synovial fluid.J. Pharm. Pharmacol. 34:410.

    Google Scholar 

  72. Lands, W. E. M., andA. M. Hanel. 1983. Inhibitors and activators of prostaglandin biosynthesis.In The prostaglandins and related compounds. C. R. Pace-Asciak and E. Granström, editors. New Comprehensive Biochemistry. Elsevier/North Holland, Amsterdam.5:203–233.

    Google Scholar 

  73. Metz, S. A. 1981. Anti-inflammatory agents as inhibitors of prostaglandin biosynthesis in man.Medical Clinics North America 65:713–757.

    Google Scholar 

  74. Simon, L. S., andJ. A. Mills. 1980. Drug therapy: non-steroidal anti-inflammatory drugs (two parts).N. Engl. J. Med. 302:1179–1185; 1237–1243.

    Google Scholar 

  75. Kuehl, F. A., Jr., J. L. Humes, E. A. Ham, R. W. Egan. andH. W. Doughehty. 1980. Inflammation: The role of peroxidase-derived products.Adv. Prostaglandin Thromboxane Res. 6:77–86.

    Google Scholar 

  76. Gryglewski, R., B. Panczenko, R. Korbut.L. Grodzinska, andA. Ocetkifwicz. 1975. Corticosteroids inhibit prostaglandin release from perfused mesenteric blood vessels of rabbit and from perfused lungs of sensitised guinea-pig.Prostaglandins 10:343–355.

    Google Scholar 

  77. Hong, S. C. L., andI. Levine. 1976. Inhibition of arachidonic acid release from cells as the biochemical action of anti-inflammatory steroids.Proc. Nail. Acad. Sci. USA 73:1730–1734.

    Google Scholar 

  78. Flower, R. J., andG. J. Blackwell. 1979. Anti-inflammatory steroids induce biosynthesis of a phospholipase inhibitor which prevents prostaglandin interaction.Nature 278: 456–459.

    Google Scholar 

  79. Hirata, F., E. Schjffmann, andK. Venkatasubramanian. 1980. A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids.Proc. Natl. Acad. Sci. USA 77:2533–2536.

    Google Scholar 

  80. Granström, E. 1983. Biochemistry of the prostaglandins. thromboxanes and leukotrienes.In Advances in Pain Research and Therapy. J. J. Bonica. U. Lindblom and A. Iggo. editors. Raven Press. New York. 605–615.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

This review was supported by grants from the Swedish Medical Research Council (proj. no. 03P-5804).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Granström, E. The arachidonic acid cascade. Inflammation 8 (Suppl 1), S15–S25 (1984). https://doi.org/10.1007/BF00915709

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00915709

Keywords

Navigation